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The influence of the structural symmetry of the 2-pi double-reactive-sites component in the 1,3-dipolar cycloaddition reactions, involving nitrilimines as dipoles, was investigated. the experimental data showed that the loss of the symmetry leads to the formation of the monocycloadduct in good yields.

The reactivity of asymmetric benzo-condensed diazines in the 1,3-dipolar cycloaddition reactions with nitrilimines was investigated. The results demonstrated that, at variance with the symmetric quinoxaline, a certain grade of diastereoselectivity emerged. Moreover in the case of the 5-methylquinoxaline and quinazoline a mono-cycloadduct was obtained.

A series of derivatives of new ring system pyrido[4’,3’:4,5]pyrrolo[2,1-d] [1,2,3,5]tetrazine was obtained from moderate to excellent yields by reaction of 2-diazo-3-ethoxycarbonyl-pyrrolo[2,3- c]pyridine with alkyl- or aryl-isocyanates in dichlorometane at room temperature or at 50 °C under microwave irradiation.

Twelve derivatives of new ring system pyrido[2’,3’:4,5]pyrrolo[2,1-d][1,2,3,5]tetrazine were prepared in good yields by reaction of 2-diazo-3-ethoxycarbonyl-pyrrolo[3,2-b]pyridine with alkyl- or aryl-isocyanates. Nine derivatives, screened by the National Cancer Institute (Bethesda, MD) for the in vitro one dose primary anticancer assay against a panel of about 60 human tumor cell lines, showed no significant activity.

Various derivatives of the heterocyclic system 1,12,12a,12b-tetrahydrobis-1,2,4-triazolo[4,3-a:3′,4′-c]quinoxaline of pharmaceutical interest have been obtained by double site- and regio-selective 1,3-dipolar cycloaddition of arylnitrilimines to quinoxalines. No evidence for the formation of mono-adducts was obtained, at variance with literature reports. Specific studies to establish the exact stereochemistry of the bis-cycloadducts were undertaken.

The title indolo-triazolo-pyrimidines were obtained from 3-azidoindoles and can be used as models for the design of DNA-interactive compounds. Hetero-domino reaction of azidoindoles/pyrroles and acetonitriles constitutes the synthetic entry to annelated 1,2,3-triazolo[1,5- a ]pyrimidines.

The aim of this work was devoted to develop a method to predict Delta G values for a series of minor groove binders. Starting from a matrix of docking dataset for 10 minor groove binders (known and not) to 20 DNA fragments, with various sequences, it was possible to analyze the interaction modes and to calculate the Delta G value for new derivatives through MADoSPRO procedure. The method allowed, through the QSPR analysis, to characterize the type of interactions in such complexes, that was demonstrated to be related to quantum chemical and electrostatic descriptors, in agreement with the information available in literature on the structural requirements of specific minor groove ligands. Moreover it was possible also to design new ligands with different lengths and enedine spacers to modulate the binding affinity with various nucleotide sequences. It was observed that in some cases it was possible to increase the affinity toward GC base-pairs notoriously not favoured for most of groove binders.

Drug design was performed through the Virtual Lock-and-Key (VLAK) protocol. This in silico approach allowed to select new annelated thienotriazolopyrimidine derivatives, potentially antitumor drugs. Starting from benzothieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine and Pyrido[3',2':4,5]thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine core structures, new derivatives of these nuclei were designed and synthesized. Three of them were selected by the Development Therapeutical Program (DTP) of the National Cancer Institute (NCI) for the anticancer screening against a panel of 60 human tumor cell lines. The biological results showed that the new derivatives exhibited an excellent antiproliferative activity reaching sub-micromolar concentration. Moreover, to be evidenced their low toxicity and high potency.

Isoindoloquinoxalines 4 and 5 were obtained by refluxing 2-(2'-aminoaryl)-1-cyanoisoindoles 3a- e in acetic or formic acid. All derivatives were screened by the National Cancer Institute (Bethesda, MD) for the in vitro one dose primary anticancer assay against a 3-cell line panel. Compounds 4a- e, screened against a panel of about 60 human tumor cell lines, showed remarkable antineoplastic activity; they had GI 50 values in the low micromolar or submicromolar range and reached, in the case of 4c, nanomolar concentrations on 88% of the 59 tested cell lines. Flow cytometric analysis of cell cycle after treatment with 4c demonstrated an arrest of the cell cycle in G2/M phase. This effect was accompanied with apoptosis of the cells, mitochondrial depolarization, generation of reactive oxygen species, and activation of caspase-3 and caspase-9. Moreover, 4c induced a clear increase in the mitotic index, inhibited microtubule assembly in vitro, and interestingly also acted as a topoisomerase I inhibitor.

New derivatives of the indolo[3,2- e][1,2,3]triazolo[1,5- a]pyrimidine system, substituted in the 4 position, were designed as novel antitumor agents because of their theoretical capability to form stable complexes with DNA fragments. The calculated free energies of binding were found in the range -12.76 --> -39.68 Kcal/mol. The docking studies revealed a common binding mode with the chromophore intercalated between GC base pairs, whereas the side chain lies along the minor groove. Compounds, selected on the basis of the docking studies and suitably synthesized, showed antiproliferative activity against each type of tumor cell line investigated, generally in the low micromolar range. The more active derivatives were shown to be 1eJ and 1eL, endowed with significant antiproliferative activity against the renal and CNS subpanels, respectively. A mechanism of action closely related to the DNA-interacting drugs can be supposed, although, alternative mechanisms, similar to those of the anthracyclines, can also operate.